PROJECT SUMMARY Colorectal Cancer (CRC) is the third-most common malignancy for men or women. There are a number of known risk factors associated with CRC including inflammatory bowel diseases, diet, and obesity with the underlying cause behind these risk factors being chronic low grade inflammation. Additionally, epidemiological research has convincingly shown that obesity increases colorectal cancer (CRC) risk, with generally stronger associations observed in men than in women, suggesting that sex hormones may play a role. Macrophages (M?s) are a major player in the inflammatory response and are not only the most abundant immune population in a tumor microenvironment but also are a driving force in obesity-associated inflammation leading to metabolic dysfunction. While it is well established that macrophages can be primary contributors to protumoral processes, their mechanism for promoting tumor growth throughout various stages of CRC is not clear. In addition sex differences in the role of macrophages during obesity driven CRC is severely understudied. I am proposing to elucidate the role of M?s in CRC and obesity, and further, the interaction between M?s, obesity, and sex differences in CRC (F99 phase). Understanding the role of M?s and their mechanism of action in metabolic dysfunction and the progression of CRC will translate to the development of more effective prevention/treatment approaches. My data indicates that depleting macrophages in late stage CRC can decrease tumor number and macrophage associated inflammation in the colon. Additionally, I report that reducing macrophages following diet induced insulin resistance does not ameliorate metabolic function and may result in anemia and neutrophilia, contrary to previous reports. I also expect to uncover unique macrophage behaviors with in sex specific and/or obesity driven CRC. Emerging evidence identifies macrophage metabolism as a promising target for therapeutic intervention in cancer and other inflammatory diseases. Tumor associated macrophages (TAM) can represent up to 50% of a tumor mass and are correlated with poor prognosis. Despite the dominating presence of TAMs in the cancer state, their phenotype and metabolic profiles remain unclear; thus, highlighting the need for more specific approaches for characterizing the heterogeneous TAMs populations. Additionally, TAMs exhibit a unique metabolism and have the ability to reprogram their metabolic phenotype to survive depending on their environment. There is promising evidence that manipulation of glycolysis or fatty acid oxidation can reprogram TAMs toward an antitumor phenotype and provide a unique strategy for cancer immunotherapy. The goal of the K00 phase is to uncover the mechanisms linking TAM metabolism to cancer progression so that therapeutic targets can be developed.